Obesity has emerged as one of the most critical health care problems in the US as 69% of the US population is currently overweight or obese. Adipose tissue dysfunction is an essential hallmark linking obesity to the pathogenesis of cardiometabolic disease, and prior work form our group has demonstrated that qualitative properties of adipose tissue shape systemic phenotypes. In particular, impaired adipose tissue angiogenesis in obesity has been associated with inflammation and metabolic dysfunction; however pathogenic mechanisms are incompletely understood. We describe a novel endogenous isoform of vascular endothelial growth factor (VEGF-A), VEGF-A165b that is selectively over-expressed in obesity and inhibits angiogenesis. Our preliminary data suggest that perturbations in the Wnt5a signaling system up-regulates VEGF-A165b under conditions of obesity that is modified by bariatric surgical weight loss. In aim 1, we will examine adipose depot-specific microvascular angiogenic responses in biopsied fat samples from 150 obese and 50 lean subjects. We will characterize VEGF-A isoforms in relation to angiogenic capacity and vascularization. We hypothesize that inhibitory isoform VEGF-A165b will be up- regulated in obesity, associated with anti-angiogenic actions in fat, and relate to whole body metabolic dysfunction. In aim 2, specific inhibitors of Wnt signaling will be employed using human adipose tissue samples secured from aim 1 to provide a molecular framework for understanding the regulation of VEGF-A 165b expression. In aim 3, we will re-examine adipose angiogenic capacity and VEGF isoform expression at 6 months following bariatric surgery in the same 150 obese subjects from aim 1. We will test whether relevant molecular pathways specifically identified in aim 2 are influenced by weight reduction. We seek to identify novel determinants of adipose tissue biology and angiogenesis in relation to metabolic changes which will develop in association with marked weight loss in obese individuals. Our proposal may identify the Wnt5a-VEGF-A 165b axis as a novel modulator of angiogenesis, adipose tissue biology, and consequently, systemic disease in clinical obesity and potentially lead to the identification of new therapeutic targets.